Clinical imaging technology plays a significant role in diagnosis of injuries and disease processes. Virtually any part of an animal's body can now be examined for diagnostic purposes using a variety of imaging techniques. Radiography has long been used to image body parts through which externally generated x-rays are transmitted. Computerized axial tomography (CAT) provides cross-sectional x-ray images of a plane of the body. Specific tissues or organs may be targeted in positron emission tomography (PET), single photon emission computed tomography (SPECT), and scintigraphy. In PET, SPECT, and scintigraphy, radiopharmaceutical agents capable of sequestering to some degree in the target tissue or organ are internally administered to the patient, and images are generated by detecting the radioactive emissions from the sequestered radiopharmaceutical agent. Radiopharmaceutical agents include nuclides such as 201Tl, 99mTc, 133Xe, and the like; chelates of nuclides; nuclide labeled metabolic agents such as 11C-deoxy-D-glucose, 18F-2-fluorodeoxy-D-glucose, [1-11C]- and [123I]-β-methyl fatty acid analogs, 13N-ammonia, and the like; infarct avid agents such as 99mTc-tetracycline, 99mTc-pyrophosphate, 203Hg-mercurials, 67Ga-citrate, and the like; and nuclide labeled monoclonal antibodies. Whole cells such as erythrocytes and leukocytes may also be labeled with a radionuclide and function as radiopharmaceutical agents.
The amount and type of clinical information that can be derived from PET, SPECT, and scintigraphic images is related in part to the ability of the radiopharmaceutical agent to sequester in the target tissue or organ. Although many radiopharmaceuticals are available for clinical use, for a given imaging instrument, the agents generally have limitations in the resolution of the image generated. The resolution available for a particular imaging agent is highly dependent on the affinity of the radiopharmaceutical to bind at the site of injury as compared to the affinity of the radiopharmaceutical to bind to healthy tissue surrounding the site of injury.
In spite of their limitations, radiopharmaceuticals are used in a variety of types of studies to obtain different kinds of information. For example, radiopharmaceutical agents used in cardiac blood flow and blood pool studies provide information on murmurs, cyanotic heart disease, and ischemic heart disease. Perfusion scintigraphy agents provide measurements of blood flow useful in detection of coronary artery disease, assessment of pathology after coronary arteriography, pre- and postoperative assessment of coronary artery disease, and detection of acute myocardial infarction. Infarct avid agents are used for “hot spot” infarct imaging. Radiopharmaceuticals which allow binding to specific cardiac receptors, while generally still in the developmental stage, may allow detection of highly specific binding in the cardiovascular system. Radionuclide-containing antibodies directed against the heavy chain of cardiac myosin have been proposed to identify zones of acute myocardial necrosis, and 99mTc-labeled low density lipoprotein may be useful to detect atheromatous lesions in their early stages after onset of endothelial damage. 99mTc-HMPO and 123I-iodoamphetamines are used to study changes in brain blood flow with SPECT. Receptor-ligand interactions, glucose utilization, protein synthesis, and other physiological parameters are also studied with other radiopharmaceuticals using PET.
Radiopharmaceutical agents capable of detecting the rate and amount of metabolism are particularly important to the progress of clinical nuclear medicine, since they allow studies of the energy consumption in the various stages of disease processes. For example, cardiac metabolism can now be studied using labeled physiologic tracers and using analogs of “natural” metabolites that are transported in the same manner as the metabolite but go through only a few reactions of the metabolic pathway and are then trapped in the tissue in a chemically known form. The glucose analog [18F]-2-fluoro-2-deoxy-D-glucose can be used to detect areas of altered glucose metabolism in the heart or other target organs which may be associated with hypoxia and anoxia and thus aid in defining the extent of an ischemic injury or cardiomyopathy. Fatty acids are the main source of energy for the heart, and radiolabeled fatty acids or their close analogs have been used to study heart metabolic integrity. β-methyl-fatty acid analogs are one group of fatty acids used as metabolic tracers.
Racemic mixtures of many β-methyl-fatty acid analogs are disclosed in U.S. Pat. No. 4,524,059. One β-methyl-fatty acid analog, [123I]-15-(p-iodophenyl)-3-R,S-methylpentadecanoic acid ([123I]-BMIPP) has been used for myocardial imaging in Japan. However, the racemic nature of [123I]-BMIPP makes it less than optimal for imaging studies, since uptake and metabolism of the R and S stereoisomers may differ and thus decrease the specificity of the reagent for heart tissue. Although use of stereoisomers of β-methyl-fatty acid analogs has been suggested, obtaining such isomers at a meaningful level of purity has been difficult.
Because an accurate imaging diagnosis of injury or disease depends so heavily on the agent used, a need continues to exist for radiopharmaceuticals with improved tissue and organ specificity.